t

Biopharmaceutics and
Clinical Pharmacokinetics
MILO GIBALDI, PH. D.
Dean, School of Pharmacy
Associate VicePresident,
Health Sciences
University of Washington
Seattle, Washington

FOURTH EDITION

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LEA & FEB1GER • Philadelphia • London 1991 is

APOTEX - EXHIBIT 1034
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i Lea & Febiger Lea & Febiger (UK) Ltd.
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Library of Congress Cataloging-in-Publication Data
It Gibaldi, Mile.
Biopharmaceutics and clinical pharmacokinetics / Milo Gibaldi.—
4th ed.
p. cm.
o Includes bibliographical references.
I- ISBN 0-8121-1346-2
1. Biopharmaceutics. 2. Pharmacokinetics. 1. Title
'P
[DNLM: 1. Biopharmaceutics. 2. Pharmacokinetics. QV 38 G437b]
RM301.4.G53 1990
615'. 7—dc20
j1.
DNLM/DLC
for Library of Congress 90-5614
CIP

First Edition, 1971

Reprinted 1973, 1974, 1975
Second Edition, 1977
Reprinted 1978, 1979, 1982
Third Edition, 1984
Reprinted 1988
Fourth Edition, 1991
First Spanish Edition, 1974
First Japanese Edition, 1976
Second Japanese Edition, 1981
Second Turkish Edition, 1981

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supplement.

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PRINTED IN THE UNITED STATES OF AMERICA

Print no.: 4 3 2 1
 Contents

Introduction to Pharmacokinetics

2 Compartmental and Noncompartmental

Pharmacokinetics 14

Gastrointestinal Absorption—
Biologic Considerations 24

A Gastrointestinal Absorption—
Physicochemical Considerations 40

Gastrointestinal Absorption—
Role of the Dosage Form 61

6. Nonoral Medication 80

Prolonged-Release Medication 124

g Bioavailability 146

9. Drug Concentration and Clinical Response 176

10. Drug Disposition—Distribut ion 187

11. Drug Disposition—Eliminat ion (203 /

ix
 :1\

1\
Contents

.V

12. Pharmacokinetic Variability—

Body Weight, Age, Sex, and Genetic Factors 234
&

I 272
13. Pharmacokinetic Variability—Disease

14. Pharmacokinetic Variability—Drug Interactions 305

• 5

15. Individualization and Optimization of

f |

Drug Dosing Regimens 344

•p

Appendix I. Estimation of Area Under the Curve 377

Appendix II. Method of Superposition 379

Index 381

Introduction to Pharmacokinetics
Advancements in biopharmaceutics have come
about largely through the development and appli­
cation of pharmacokinetics. Pharmacokinetics is
i
the study and characterization of the time course
of drug absorption, distribution, metabolism, and
excretion, and the relationship of these processes
to the intensity and time course of therapeutic and
toxicologic effects of drugs. Pharmacokinetics is
used in the clinical setting to enhance the safe and
effective therapeutic management of the individual
patient. This application has been termed clinical
pharmacokinetics.
DISTRIBUTION AND ELIMINATION
The transfer of a drug from its absorption site
to the blood, and the various steps involved in the
distribution and elimination of the drug in the body,
are shown in schematic form in Figure 1-1. In the
blood, the drug distributes rapidly between the
plasma and erythrocytes (red blood cells). Rapid
distribution of drug also occurs between the plasma
proteins (usually albumin but sometimes ctj-acid
glycoproteins and occasionally globulin) and
plasma water. Since most drugs are relatively small
molecules they readily cross the blood capillaries
and reach the extracellular fluids of almost every
organ in the body. Most drugs are also sufficiently
lipid soluble to cross cell membranes and distribute
in the intracellular fluids of various tissues.
Throughout the body there is a distribution of drug
between body water and proteins or other macro-
molecules that are dispersed in the body fluids or
are components of the cells.
The body can be envisioned as a collection of
separate compartments, each containing some frac­
tion of the administered dose. The transfer of drug
from one compartment to another is associated with
) 1
1
a rate constant (k). The magnitude of the rate con­
stant determines how fast the transfer occurs.
The transfer of drug from blood to extravascular
fluids (i.e., extracellular and intracellular water) i
and tissues is called distribution. Drug distribution
is usually a rapid and reversible process. Fairly
quickly after intravenous (iv) injection, drug in the
plasma exists in a distribution equilibrium with
drug in the erythrocytes, in other body fluids, and
in tissues. As a consequence of this dynamic equi­
librium, changes in the concentration of drug in
the plasma are indicative of changes in drug level
in other tissues including sites of pharmacologic
effect (bioreceptors).
The transfer of drug from the blood to the urine
or other excretory compartments (i.e., bile, saliva,
and milk), and the enzymatic or biochemical trans­
formation (metabolism) of drug in the tissues or
plasma to metabolic products, are usually irre­
versible processes. The net result of these irre­
versible steps, depicted in Figure 1-1, is called
drug elimination. Elimination processes are re­
sponsible for the physical or biochemical removal
of drug from the body.
The moment a drug reaches the bloodstream, it
is subject to both distribution and elimination. The
rate constants associated with distribution, how­
ever, are usually much larger than those related to
drug elimination. Accordingly, drug distribution
throughout the body is usually complete while most
of the dose is still in the body. In fact, some drugs
attain distribution equilibrium before virtually any
of the dose is eliminated. In such cases, the body
appears to have the characteristics of a single com­
partment.
This simplification, however, may not be applied
to all drugs. For most drugs, concentrations in
plasma measured shortly after iv injection reveal a
 i
I
'I-
•J 2 Biopharmaceutics and Clinical Pharmacokinetics
•ft
w.
Drug at
4 > Drug in Blood
n Absorption Site
^1
Drug in
Other Fluids
of Distribution
:•
Fig. 1-1. Schematic representation of drug absorption, distribution, and elimination.
distinct distributive phase. This means that a meas­
urable fraction of the dose is eliminated before
attainment of distribution equilibrium. These drugs
impart the characteristics of a multicompartment
system upon the body. No more than two com­
partments are usually needed to describe the time
course of drug in the plasma. These are often called
the rapidly equilibrating or central compartment
and the slowly equilibrating or peripheral com­
partment.
PHYSICAL SIGNIFICANCE OF DRUG
CONCENTRATION IN PLASMA
Blood samples taken shortly after intravenous
administration of equal doses of two drugs may
show large differences in drug concentration de­
spite the fact that essentially the same amount of
each drug is in the body. This occurs because the
degree of distribution and binding is a function of
the physical and chemical properties of a drug and
may differ considerably from one compound to
another.
At distribution equilibrium, drug concentrations
in different parts of the body are rarely equal. There
may be some sites such as the central nervous sys­
tem or fat that are poorly accessible to the drug.
There may be other tissues that have a great affinity
for the drug and bind it avidly. Drug concentrations
at these sites may be much less than or much greater
than those in the plasma.
Despite these complexities, once a drug attains
distribution equilibrium its concentration in the
plasma reflects distribution factors and the simple
relationship between amount of drug in the body
(A) and drug concentration in the plasma (C) shown
in Equation 1-1 applies:
A = VC (1-1)
Drug in Urine
k4
^5
Metabolite(s)
^6
^2 k_ 2
Drug in Other
Excretory Fluids
k3 , Drug in
k_3 Tissues
The proportionality constant relating amount and
concentration is called the apparent volume of dis­
tribution (V). In most situations, V is independent
of drug concentration. Doubling the amount of
drug in the body (e.g., by doubling the iv dose)
usually results in a doubling of drug concentration
in plasma. This is called dose proportionality; it
is often used as an indicator of linear pharmaco­
kinetics.
The apparent volume of distribution is usually a
characteristic of the drug rather than of the biologic
system, although certain disease states and other
factors may bring about changes in V. The mag­
nitude of V rarely corresponds to plasma volume,
extracellular volume, or the volume of total body
water; it may vary from a few liters to several
hundred liters in a 70-kg man. V is usually not an
anatomic volume but is a reflection of drug distri­
bution and a measure of the degree of drug binding.
Acid drugs, such as sulfisoxazole, tolbutamide,
or warfarin, are often preferentially bound to
plasma proteins rather than extravascular sites. Al­
though these drugs distribute throughout body wa­
ter, they have small volumes of distribution ranging
from about 10 to 15 L in man. A given dose will
result in relatively high initial drag concentrations
in plasma.
On the other hand, many basic drugs including
amphetamine, meperidine, and propranolol are
more extensively bound to extravascular sites than
to plasma proteins. The apparent volumes of dis­
tribution of these drugs are large, ranging from 4
to 8 times the volume of total body water (i.e..
180 to 320 L in a 70-kg man). The frequently small
doses and large distribution volumes of these drugs
often make their quantitative detection in plasma
difficult.
I Introduction to Pharmacokinetics 3

100 tion rate falls in parallel. The proportionality con­

dAA/dt=dAE/dt stant relating rate and amount or concentration is
C called a rate constant. Accordingly, the elimination
to
80 \ dAA/dt<dAE:/dt
o rate is written as follows;
O
60 - dA dAE
o — = kA (1 -2)
dt dt
c 40 - ^-dAA/dt =0
where A is the amount of drug in the body at time
o
t, Ae is the amount of drug eliminated from the
S; 20 B body (i.e., the sum of the amounts of metabolites
CL dAA/dt > dAE/dt
that have been formed and the amount of drug
iA excreted) at time t, and k is the first-order elimi­
4 8 12 16 20 nation rate constant.
Time (hrs) The elimination rate constant is the sum of in­
f dividual rate constants associated with the loss of
Fig. 1-2. Time course"of drug disappearance from the
parent drug. For example, the overall elimination
absorption site (curve A) and appearance of eliminated drug
in all forms (curve C). The net result is curve B, which
rate constant (k) in the model depicted in Figure
depicts the time course of drug in the body. 1-1 is given by

k = k4 + kj + k5 (1-3) •
PHARMACOKINETIC CONSIDERATIONS OF
DRUG CONCENTRATIONS IN PLASMA Dimensional analysis of Equation 1-2 indicates
that the units of k are reciprocal time (i.e., day
The plasma contains measurable quantities of
hr1, or mhr1).
many endogenous chemicals. In healthy individ­
Since there is a relationship between the amount
uals these biochemicals are present in concentra­
of drug in the body and the drug concentration in
tions that are reasonably constant, and it is appro­
the plasma (Eq. 1-1), we may rewrite Equation
priate to speak of creatinine or bilirubin levels in
, 1-2 as
the plasma. Drug levels or concentrations in the
plasma are rarely level. One usually finds different d(VC) dC
= -V— = k(VC)
concentrations of drug in the plasma at different dt dt
times after administration. These changes reflect
the dynamics of drug absorption, distribution, and or
elimination (Fig. 1-2). dC
— = kC (1-4)
I
dt
Intravenous Administration
Absorption need not be considered when a drug Integrating this expression between the limits t =
is given by rapid iv injection. As soon as the drug 0 and t = t yields
is administered it undergoes distribution and is sub­ kt
ject to one or more elimination pathways. The log C = log C0 (1-5)
2.303
amount of drug in the body and the drug concen­
tration in plasma decrease continuously after in­
jection. At the same time, there is continuous for­
Equation 1-5 indicates that a plot of log C versus
t will be linear once distribution equilibrium is
is
mation of metabolites and continuous excretion of reached. The term C0 is the intercept on the log
drug and metabolites. Eliminated products accu­ concentration axis, on extrapolation of the linear
mulate while drug levels in the body decline. segment to t = 0.
Most drugs distribute rapidly so that shortly after
iv injection, distribution equilibrium is reached.
Figure 1-3 shows the average concentration of
a semisynthetic penicillin in the plasma as a func­ I
Drug elimination at distribution equilibrium is usu­ tion of time after an intravenous injection of a 2-g
ally described by first-order kinetics. This means dose. The concentration values are plotted on a log
that the rate of the process is proportional to the scale; the corresponding times are plotted on a lin­
amount or concentration of substrate (drug) in the ear scale. The semilogarithmic coordinates make
system. As drug concentration falls, the elimina- it convenient to plot first-order kinetic data for they
I
'!
>

4 Biopharmaceutics and Clinical Pharmacokinetics

It1
•

is much easier to determine k by making use of

the following relationship;
200 -
Co k = 0.693/tw (1-7)
E \

t) where tw is the half-life of the dmg (i.e., the time

o*
4
zr 100 ~
\ required to reduce the concentration by 50%). This
parameter is determined directly from the plot (see
O k Fig. 1-3). In a first-order process, the half-life is
Slope= „
f-m H
< fcv' 2.303
independent of the dose or initial plasma concen­
cn
h- tration. One hour is required to observe a 50%
2 50 -
1
ti
LU
o
decrease of any plasma concentration of the semi­
synthetic penicillin, once distribution equilibrium
V 2 is attained. It follows that the elimination rate con­
o
•'r o stant of this drug is equal to 0.693/t^ or 0.693 hr'.
ij
CD Knowledge of the half-life or elimination rate con­
tl, ' I hr
23 20 -
ii (T 'z stant of a drug is useful because it provides a quan­
. * Q titative index of the persistence of drug in the body.

k o For a drug that distributes very rapidly after iv

10 i i
I 2 3 4
TIME, hr
:(*•
;\s Fig. 1—3. Semilogarithmic plot of penicillin concentra­
;•( tions in plasma after a 2-g intravenous dose. Concentrations
v-q1 decline in a first-order manner with a half-life of 1 hr.
'
avoid the necessity of converting values of C to
logC.
According to Equation 1-5, the linear portion
of the semilogarithmic plot of C versus t has a
slope corresponding to ~k/2.303 and an intercept,
on the y-axis (i.e., at t = 0), corresponding to C0.
If a drug were to distribute almost immediately
after injection, C0 would be a function of the dose
and the apparent volume of distribution. Therefore,
we would be able to calculate V as follows;
iv dose
V =
C0
For the data shown in Figure 1-3 we can determine
that C0 = 200 mg/ml and that V = 10 L.
This approach, however, is seldom useful; Equa­
tion 1-6 usually gives a poor estimate of V, always
larger and sometimes substantially larger than the
true volume of distribution. Equation 1-6 assumes
that drug distribution is immediate, whereas most
drugs require a finite time to distribute throughout
s the body space. Other methods to calculate V will
be described subsequently.
Although it is possible to calculate the elimi­
;l nation rate constant from the slope of the line, it
injection and is eliminated by first-order kinetics,
one-half the dose will be eliminated in one half-
life after administration; three-quarters of the dose
will be eliminated after two half-lives. Only after
four half-lives will the amount of drug in the body
be reduced to less than one-tenth the dose. For this
reason, the half-life of a drug can often be related
to the duration of clinical effect and the frequency
of dosing.
Short-Term Constant Rate Intravenous
Infusion
Few drugs should be given as a rapid intravenous
injection (bolus) because of the potential toxicity
that may result. Many drugs that require intrave­
nous administration, including theophylline, pro­
cainamide, gentamicin, and many other antibiotics,
are given as short-term constant rate infusions over
5 to 60 min, or longer. The following scheme de­
scribes this situation;
(1-6)
Drug in Constant Drug in k Eliminated
reservoir rate body drug
The rate of change of the amount of drug in the
body (A) during infusion is given by
dA/dt = k0 - kA (1-8)
where k0 is the infusion rate expressed in amount
per unit time (e.g., mg/min), kA is the elimination
rate, and k is the first-order elimination rate con­
stant. This relationship assumes that the drug
reaches distribution equilibrium quickly. Integrat­
ing Equation 1-8 from t = 0 to t = t yields
A = k0[l - exp(-kt)]/k (1-9)

I vij
 Introduction to Pharmacokinetics 5
• I
since all other terms are known. This estimate may
I
be less than accurate but it is always better than
that provided by Equation 1-6.
Z The maximum or peak drug concentration in
o c plasma is always lower after intravenous infusion L
H O
than after bolus injection of the same dose. The
< c T'

more slowly a fixed dose of a drug is infused, the

cc
H
Z
o
o
O)
lower the value of C max Consider a rapidly dis­
1 I
ui tributed drug with a half-life of 3 hr. A given dose
o
O administered as an iv bolus results in an initial s

Z plasma level of 100 units. The same dose, infused

O I
O over 3 hr (T = tw) gives a Cmax value of 50 units
(Cmax/2); infused over 6 hr (T = 2tw), it gives a
(D
D concentration of 25 units (Cmax/4). Also, since Cmax f
oc time is a linear function of k0, doubling the infusion rate
a and infusing over the same period of time (i.e.,
doubling the dose) doubles the maximum concen­
tration.
i i
2 4 6 8 Extravascular Administration
TIME A more complex drug concentration-time profile
is observed after oral, intramuscular, or other ex­
Fig. 1-4. Drug concentration in plasma during and after travascular routes of administration because ab­
a 1-hr constant rate intravenous infusion. The inset shows
sorption from these sites is not instantaneous, nor
the same data, plotted on semilogarithm ic coordinates.
does it occur at a constant rate. As shown in Figure 1
1-2, the rate of change of the amount of drug in
or
the body (dA/dt) is a function of both the absorption 1)
C - k0[l - exp(-kt)]/kV (1-10) rate (dAA/dt) and the elimination rate (dAE/dt); that
is,
According to Equation 1-10, drug concentration
in plasma increases during infusion. When the en­ dA dAA dAE
(1-14)
tire dose has been infused at time T, drug concen­ dt dt dt
tration reaches a maximum given by
or
Cmax = k0[l - exp( —kT)]/kV (1-11)
dC _ dAA dAE
and thereafter declines. The declining drug con­ (1-15)
dt _ V dt dt
centration is described by
where V is the apparent volume of distribution.
C = Cmax exp(-kt') (1-12)
When the absorption rate is greater than the elim­
)
or ination rate (i.e., dAA/dt > dAF/dt), the amount of j '
drug in the body and the drug concentration in the
log C = log Cmax - (kt72.303) (1-13)
plasma increase with time. Conversely, when the
where t' = t —T. Equations 1-12 and 1-13 apply amount of drug remaining at the absorption site is I
;ii ;

when distribution equilibrium is essentially reached
by the end of the infusion. A semilogarithmic plot
of C (post-infusion drug concentration in plasma)
versus t' yields a straight line, from which the half-
life and elimination rate constant can be estimated.
The entire drug concentration-time profile during
sufficiently small so that the elimination rate ex­
ceeds the absorption rate (i.e., dAE/dt > dAA/dt),
the amount of drug in the body and the drug con­
11 *
centration in the plasma decrease with time. The
III I
maximum or peak concentration after drug admin­ i; i
istration occurs at the moment the absorption rate 'M

and after a short-tenn infusion is shown in Figure equals the elimination rate (i.e., dAA/dt = dAE/dt).
1-4. The faster a drug is absorbed, the higher is the
Equation 1-11 may be arranged to calculate V, maximum concentration in plasma after a given

I
6 Biopharmaceutics and Clinical Pharmacokinetics i

dose, and the shorter is the time after administration T T T

when the peak is observed.

E
First Order In—First Order Out
CJ> 50 -
Many drugs appear to be absorbed in a first- Start of po»t- 11 [
order fashion and the following scheme often ap­ z \ abtorptive phase
o
plies; g
ct
Drug at Drug in ^ ^ Eliminated r- Sl0P'"
z IS*/
absorption site body drug UJ
Z 2.0 -
Under these conditions O
o

dA/dt kaAA - kA (1-16) o k— 11 —>1

where ka is the apparent first-order absorption rate
constant, k is the first-order elimination rate con­
stant, A is the amount of drug in the body, and A A
is the amount of drug at the absorption site. Inte­
grating Equation 1-16 from t - 0 to t = t and
converting amounts to concentrations results in the
complicated equation shown below:
C = kaFD[exp( - kt)
- exp( —kat)]/V(ka - k)
where F is the fraction of the administered dose
(D) that is absorbed and reaches the bloodstream,
V is the apparent volume of distribution, and C is
the drug concentration in plasma any time after
administration. Equation 1-17 is often used to de­
scribe drug concentrations in plasma after extra-
vascular administration.
The absorption rate constant of a drug is fre­
quently larger than its elimination rate constant. In
this case, at some time after administration, the
absorption rate term in Equation 1-15 approaches
zero, indicating that there is no more drug available
for absorption, and Equation 1-17 simplifies to
C = kJFD[exp( — kt)]/V(ka - k)
or
C = C0* exp(-kt)
and
kt
log C = log C0* -
2.303
Equation 1-18 assumes that distribution equilib­
rium is essentially reached by the end of the ab­
sorption phase.
When absorption is complete, the rate of change
of the amount of drug in the body equals the elim-
ZD
cc 'l
Q
10 -
i i 1
4 8 12 16 20 I
TIME, hr
Fig. 1-5. Typical semilogarithmic plot of drug concentra­
tion in plasma following oral or intramuscular administra­
tion of a slowly absorbed form of the drug.
(1-17)
ination rate, and Equation 1-15 reduces to Equa­
tion 1-4. The portion of a drug concentration in
the plasma versus time curve, commencing at the
>r
time absorption has ceased, is called the postab-
sorptive phase. During this phase, the decline in
drug concentration with time follows first-order-
kinetics. A semilogarithmic plot of drug concen­
tration in the plasma versus time after oral or other
extravascular routes of administration usually
shows a linear portion that corresponds to the post-
absorptive phase. A typical plot is shown in Figure
1-5; the slope of the line is equal to -k/2.303.
The intercept of the extrapolated line (C0*) is a
complex function of absorption and elimination
rate constants, as well as the dose or amount ab­
(1-18) sorbed and the apparent volume of distribution. It
is incorrect to assume that the intercept approxi­
mates the ratio of dose to volume of distribution
(1-19) unless the drug is very rapidly and completely ab­
sorbed, and displays one-compartment character­
istics (i.e., distributes immediately). This rarely
occurs.
(1-20) Occasionally, the absorption of a drug is slower
than its elimination, a situation that may be found
with drugs that are rapidly metabolized or excreted
and with drugs that are slowly absorbed because
of poor solubility or administration in a slowly
releasing dosage form. When this occurs, a semi­
logarithmic plot of drug concentration versus time
 Introduction to Pharmacokinetics
(see Fig. 1-5) after oral administration cannot be
used to estimate k or half-life because the slope is
related to the absorption rate constant rather than
the elimination rate constant. The drug must be
administered in a more rapidly absorbed form or
given intravenously.
Patient-To-Patient Variability
The time course of drug in the plasma after ad­
ministration of a fixed dose may show considerable
intersubject variability. The variability after intra­
venous administration is due to differences between
patients in distribution and elimination of the drug.
These differences may be related to disease or con­
comitant drug therapy or they may be genetic in
origin. Variability is greater after intramuscular ad­
ministration because, in addition to differences in
distribution and elimination, absorption may be
variable. Differences in absorption rate after intra­
muscular injection have been related to the site of
injection and the drug formulation. Still greater
variability may be found after oral administration.
The absorption rate of a drug from the gastroin­
testinal tract varies with the rate of gastric emp­
tying, the time of administration with respect to
meals, the physical and chemical characteristics of
the drug, and the dosage form, among other fac­
tors. Similarly, the amount of an oral dose of a
drug that is absorbed depends on biologic, drug,
and dosage form considerations. Many commonly
used drugs are less than completely available to
the bloodstream after oral administration because
of incomplete absorption @)presystemic metabo­
lism. """"" """" " '
J Absorption Rate and Drug Effects
The influence of absorption on the drug concen­
tration-time profile is shown in Figure 1-6. Ad­
ministration of an equal dose in three different dos-
age forms results in different time courses of drug
in the plasma. The faster the drug is absorbed, the
greater is the peak concentration and the shorter is
the time required after administration to achieve
peak drug levels.
Many drugs have no demonstrable pharmaco­
logic effect or do not elicit a desired degree of
pharmacologic response unless a minimum con­
centration is reached at the site of action. Since a
distribution equilibrium exists between blood and
tissues, there must be a minimum therapeutic drug
concentration in the plasma that corresponds to,
though may not equal, the minimum effective con-
7
A
c
o
o
c
<u B
o
c
o MEC
O
a» c
I
3
Q
J L
il
Time
Fig. 1-6. The effects of absorption rate on drug concen-
!
tration-time profile. The same amount of drug was given
orally with each dosage form. The drug is absorbed most
rapidly from dosage form A. Drug absorption after admin­
istration of dosage form C is slow and possibly incomplete.
The dotted line represents the minimum effective concen­
tration (MEC) required to elicit a pharmacologic effect.
centration (MEC) at the site of pharmacologic ef­
fect. Thus, the absorption rate of a drug after a
single dose may affect the clinical response. For
example, it is evident from Figure 1-6 that the
more rapid the absorption rate, the faster is the
onset of response. The drug is absorbed so slowly
from dosage form C that the minimum effective
level is never attained. No effect is observed after
a single dose, but effects may be seen after multiple
doses.
The intensity of many pharmacologic effects is
a function of the drug concentration in the plasma.
The data in Figure 1-6 suggest that administration
II
of dosage form A may evoke a more intense phar­
macologic response than that observed after ad-
ministration of dosage form B since A produces a
higher concentration of drug. When dosage form
C is considered, it is clear that an active drug may
be made to appear inactive by administering it in :t
a form that results in slow or incomplete absorp­
tion. U
it
BIOAVAILABILITY
f.
The bioavailability of a drug is defined as its rate
and extent of absorption. Rapid and complete ab­ ;
'
sorption is usually desirable for drugs used on an
acute or "as needed" basis for pain, allergic re-
8 Biopharmaceutics and Clinical Pharmacokinetics

sponse, insomnia, or other conditions. As sug­ T T T T

gested in Figure 1-6, the more rapid the absorp­

1
tion, the shorter is the onset and the greater is the CT 4 -
^.g-hr
intensity of pharmacologic response. The efficacy Z
Area = I
ml
of a single dose of a drug is a function of both the O
rate and extent of absorption. In such cases, there 1— 3 -
<
is no assurance of the bioequivalence of two dosage cr
h-
forms of the same drug simply because the amount
LU 2 -
of drug absorbed from each is equivalent; the ab­ O W- 1 hr-H
sorption rate of drug from each drug product must Z
o
also be comparable. Rapid absorption may also 0 I - ct t* -
reduce the frequency and severity of gastrointes­ (S)
tinal distress observed after oral administration of a:
certain drugs, including aspirin and tetracycline, Q
by reducing the contact time in the gastrointestinal I 2 3 4
tract. TIME, hr
Usually, a useful estimate of the relative ab­
Fig. 1-7. Typical rectilinear plot of drug concentration in
sorption rate of a drug from different drug products
the plasma following an oral dose. The area under the con­
or under different conditions (e.g., with food or centration-time plot from t = 0 to t - 4 hrs is denoted by
without food) can be made by comparing the mag­ shading.
nitude and time of occurrence of peak drug con­
centrations in the plasma after a single dose.
plasma and the same AUG, the products are hio-
equivalent.
Estimating the Extent of Absorption
The area under a drug concentration in the
The extent of absorption or relative extent of plasma versus time curve has the units of concen­
absorption of a drug from a product can be esti­ tration-time (e.g., |xg — hr/ml), and can be esti­
mated by comparing the total area under the drug mated by several methods. One method is to use
concentration in plasma versus time curve (AUG), a planimeter, an instrument for mechanically meas­
or the total amount of unchanged drug excreted in uring the area of plane figures. Another procedure,
the urine after administration of the product to that known as the "cut and weigh method," is to cut
found after administration of a standard. The stand­ out the area under the entire curve on rectilinear
ard may be an intravenous injection, an orally ad­ graph paper and to weigh it on an analytical bal­
ministered aqueous or water-miscible solution of ance. The weight thus obtained is converted to the
the drug, or even another drug product accepted proper units by dividing it by the weight of a unit
as a standard. When an iv dose is used as the area of the same paper (Fig. 1-7). The most com­
standard and the test product is given orally (or via mon method of estimating area under curves is by
some other extravascular route), we determine ab­ means of the trapezoidal rule, which is described
solute bioavailability. If, following equal doses of in Appendix I.
the test product and the iv standard, the AUG values Sometimes, single dose bioavailability studies
are the same, we conclude that the drug in the test are not carried out long enough to allow drug con­
product is completely absorbed and not subject to centrations to fall to negligible levels. We cannot
presystemic metabolism. determine directly the total AUG, only the partial
Frequently, however, the standard is an oral so­ AUG. In this case, a widely used method is to
lution or an established product. If, following equal determine the AUG from t = 0 to the last sampling
doses of the test product and standard, the AUG time (t*), by means of the trapezoidal rule, and to
values are the same, we conclude that the test prod­ estimate the missing area by means of the equation
uct is 100% bioavailable, relative to the standard;
we need use the word relative because we do not Area from t* to oo = G*/k (1-21)
know a priori that the standard is completely ab­
sorbed or completely available. When two products where G* is the drug concentration at t = t*, and
produce the same peak concentration of drug in k is the apparent first-order elimination rate con-
 Introduction to Pharmacokinetics
stant. This area must be added to the area calculated
from time zero to t* to obtain the total area under
the curve.
The total area under the drug level-time curve
for drugs eliminated by first-order kinetics is given
by
Amount of drug reaching
the bloodstream
AUC - (1-22)
k • V
It follows that the bioavailability (F) of a drug from
a drug product may be determined from the ex­
pression
(AUC) Drug
F =
product
(1-23)
(AUC)Standard
when equal doses are administered. If different
doses of the product and standard are given, the
area estimates should be scaled appropriately to
permit comparison under conditions of equivalent
doses, assuming AUC is proportional to dose.
The amount of drug excreted unchanged in the
urine (Au) after administration is given by
Au = F • Dose • (ku/k) (1-24)
where ku is the urinary excretion rate constant and
k is the overall elimination rate constant. It follows
that the fraction of the dose absorbed from a drug
product relative to that absorbed from a standard
may be calculated from the expression
(Au)Drug
F —
product
(1-25)
(Au)Standard
The usefulness of Equation 1-25 depends on
how much of the drug is eliminated by urinary
excretion, the sensitivity of the assay for drug in
urine, and the variability in urinary output of the
drug. Many drugs are extensively metabolized and
little, if any, appears unchanged in the urine. In
such cases, bioavailability is estimated from
plasma concentration data.
CONTINUOUS DRUG ADMINISTRATION
Most drugs are administered in a constant dose
given at regular intervals for prolonged periods of
time. For some of these dmgs a therapeutic plasma
concentration range has been identified. By pre­
scribing a drug in an appropriate dosing regimen,
the physician hopes to elicit a prompt and adequate
clinical response. This is often predicated upon the
prompt attainment of adequate drug concentration
in the plasma.
9
Constant Rate Infusion
It is convenient to consider first the simpler case
of continuous administration of a drug by intra­
venous infusion; this method of drug administration
results in a plasma concentration-time profile that
is similar in many ways to that found on intermit­
tent repetitive dosing. Figure 1-8 illustrates the
time course of drug concentration in plasma during
and after infusion at a constant rate. At the outset,
drug concentration increases gradually but at a di­
minishing rate. If infusion is continued, drug con­ •;
centration eventually reaches a plateau or steady
state. A steady state is reached because the amount
of drug in the body reaches a level where the elim­
il
ination rate, given by kA, is equal to the infusion
rate (k0). Whenever input rate equals output rate,
dA/dt = 0, dC/dt = 0, and steady state exists.
By considering Equation 1-10, which describes
drug concentration in plasma during constant rate
infusion, at times that are sufficiently large so that
exp( —kt) approaches zero, drug concentration at
III
steady state (Css) is given by
Css = k0/kV (1-26)
;
Since attainment of steady state often represents
the stabilization of a patient on a given course of
therapy, it is of interest to know how long it takes
to reach steady state. For drugs with pharmaco­
kinetic characteristics that can be described by a
one-compartment model (i.e., drugs that distribute
rapidly) we have a relatively simple relationship
between attainment of steady state and the half-life
of the drug. One half the steady-state concentration
is reached within a period of time equal to the half-
life of the drug. Following a period of infusion
equal to four times the half-life, the plasma con­
centration is within 10% of the eventual steady-
state concentration.
If the time to reach steady-state represents an
unacceptable delay, one may wish to use an iv '
bolus loading dose or a series of iv bolus minidoses
before starting the infusion. The loading dose is :
estimated from the ratio of infusion rate (k0) to i
elimination rate constant (k). This approach works il i •
well for most drugs given intravenously.
If one knows the drug level (Css) needed to pro­ i
duce a satisfactory response. Equation 1-26 can
be used to calculate the infusion rate (k0) needed
1
to reach the desired level. Under these conditions,
k0 = Css • k • V and loading dose = Css • V. I r1'
|<
11
Bf
 •?

f
'•<
10 Biopharmaccutics and Clinical Pharmacokinetics
I•1

Infusion
i
16n

\ VTime-4 x Half-life
12-
E
2
ill O
?l
Is H
4:1 8-
1:i (T
1— ^ T i m e=1XHalf-life
2
LU
o H a l f - l i f e , 1. 7 h r
y
Z
•Vl O 4-
O

i i
; 8 16 24 32
TIME, hr
Fig. 1-8. Drug concentration in plasma during and after prolonged constant rate Intravenous infusion. (From Gibaldi,
M., and Levy, G.: Pharmacokinetics in clinical practice. II. Applications. JAMA, 235:1987, 1976. Copyright 1976,
American Medical Association.)

Repetitive Dosing where T is the dosing interval. Equation 1-27 is

Turning now to the more common case of re­
petitive oral administration of the same dose of a
drug at regular intervals (Fig. 1-9), we find that
'
although drug accumulates in much the same way
as during constant infusion, drug concentrations in
plasma during a dosing interval first increase and
then decrease as a result of absorption, distribution,
and elimination. The magnitude of the concentra­
tion difference in a dosing interval depends on the
rates of absorption and distribution and on the half-
life of the drug; this concentration difference in­
creases with increasing absorption rate and de­
creasing half-life. Drugs with long half-lives or
slow absorption show rather constant blood levels
at steady state.
Drug concentration at any time during a dosing
interval at steady state can usually be described by
the following equation:
kaFD exp( - kt)
C
^ss —
V(ka - k) 1 - exp( - k T )
(1-27)
exp( - kat)
1 - exp( - k a T )
too complicated to be of routine use; however, if
we could estimate the maximum and minimum
drug concentrations, we would be able to charac­
terize steady state. Solving Equation 1-27 for the
maximum drug concentration at steady state yields
an equally complex equation. Better results are ob­
tained when we solve for the minimum concentra­
tion at steady state, particularly if we assume that
a dose is always given in the postabsorptive phase
of the previous dose. Under these conditions.
kaFD exp( — kx)
(^-'min)ss (1-28)
V( k a - k )[l - exp( - k T ) ]
Since the minimum drug concentration after the
first dose of a repetitive dosing regimen is given
by
Cmin = k aFD exp( - k T )/V( k a - k) (1-29)
we can write a relatively simple expression for the
degree of drug accumulation during multiple dos­
ing by comparing the minimum drug concentration
 Introduction to Pharmacokinetics 11

cmax
3CH

—c
o>

z
E
r\ \
\
mm
O
20-
H
<
a:
z
LLI
O
z
o 10-
o

I
2 3 4
1
TIME, days
maximum (C m a ,),
Fig. 1-9. Drug concentratio n in plasma during repetitive oral administratio n of 250 mg every 5 hr. The
(C ), and average (C) drug concentratio ns at steady state are noted. (From Gibaldi, M., and Levy, G.: Phar­
minimum mm
American Medical Associa-
macokinetic s in clinical practice. II. Applications . JAMA, 235:1987, 1976. Copyright 1976,
tion.)

at steady state to that after the first dose. Dividing
Equation 1-28 by Equation 1-29 yields
Accumulation = (Cmin)ss/Cmin (1-30)
= 1/[1-exp( k T ) ]
Therefore, by merely knowing the elimination rate
constant (k) or half-life of a drug we can predict
the degree of accumulation for a given dosing reg­
imen. If a drug is given every half-life (T = t^)
the accumulation at steady state will be about 2-fold
relative to the first dose.
Some drugs, including the penicillins and ceph­
alosporins, are given less frequently than once
every half-life. These drugs have half-lives in the
but they are given either several times a day or
once a day. Drug accumulation may be substantial.
When appropriate, it has become increasingly
common to administer a drug once every half-life.
The current use of theophylline, procainamide,
phenytoin, and tricyclic antidepressants reflects
this trend.
Average Drug Concentration at Steady State
An alternative and simpler way of describing
steady state is to consider the average drug con­
centration (Css), which is analogous to the steady-
state concentration during continuous infusion. If
drug concentration during each dosing interval is
viewed in terms of an average concentration, we
can express the intermittently administered dose in !

order of 1 hr, but are usually given every 6 to 8 tenns of an average dosing rate. For example, 100
hr. Virtually no accumulation is observed on re­ mg given every 4 hr can be viewed as a 25 mg/hr I* U

peated administration. Many drugs, such as diaz­ average dosing rate. When based on these consid­
:
erations, Equation 1-26 for a constant rate intra­
ih
epam, amiodarone, phenobarbital, and digoxin, are
given more frequently than once every half-life. venous infusion can be applied to the intermittent f

For these drugs the half-life is greater than one day oral administration of a drug with one additional llli
111
i> f

lit
12 Biopharmaceutics and Clinical Pharmacokinelics
provision; allowance must be made for the possi­
bility that absorption of the drug is less than com­
plete. Then,
Css = F(average dosing rate)/Vk (1-31)
where F is the fraction of the administered dose
that actually reaches the bloodstream. The prop­
erties and usefulness of Css are discussed in greater
detail in Chapter 2.
Loading Dose
Whether a drug is given by continuous intra­
venous infusion or by repetitive oral administra­
tion. it usually requires about 4 times the half-life
of the drug to reach an average concentration within
10% of the steady-state concentration. In some in­
stances, this may represent too long a period to
wait for optimum drug effects, and an initial load­
ing dose is used.
Assuming that it is clinically acceptable to do
this in a single dose, one can estimate a loading
dose based on the usual maintenance dose and elim­
ination rate constant of the drug as follows:
Maintenance dose
(1-32)
Loading dose =
1 - exp( - k T )
This loading dose will provide a drug concentration
T hr after administration that is equal to the mini­
mum drug concentration at steady state following
repetitive administration of the maintenance dose.
If a drug is administered every half-life, the ap­
propriate loading dose is 2 times the maintenance
dose. Therapy with tetracycline (t^ = 8 hr) is often
initiated with a 500-mg loading dose followed by
250 mg every 8 hr.
The difference between loading dose and main­
tenance dose depends on the dosing interval and
the half-life of the drug. Digoxin, which has a half-
life of about 44 hr but is administered once a day.
is typically given as a loading dose of 1.0 to 1.5
mg followed by daily doses of 0.125 to 0.5 mg;
the ratio of loading dose to maintenance dose is
about 3 or 4. The half-life of digitoxin is about 6
days; typically digitoxin therapy is initiated with a
loading dose of up to 1.6 mg followed by daily
doses of 0.1 to 0.2 mg; the ratio of loading dose
to maintenance dose is usually about 10. The
smaller the ratio of dosing interval to half-life, the
larger is the ratio of loading dose to maintenance
dose.
Loading of drugs may be hazardous, particularly
for those drugs which distribute slowly or to which
patients become accustomed only gradually. Cau­
tion should be applied at all times. With digoxin
or digitoxin therapy, loading (or digitalization) is
almost always carried out with 3 or 4 divided doses
over the first 1 or 2 days of therapy.
Treatment of epileptic patients with phenytoin
is often initiated with a regular maintenance dose.
divided or single, of 300 to 400 mg daily. When
phenytoin therapy is begun in this manner, steady-
state plasma phenytoin levels are achieved after 7
to 10 days. Some clinicians believe, however, that
in the patient with frequent seizures a delay in
reaching the therapeutic steady-state phenytoin
plasma level may be detrimental because attacks
may occur before the drug develops its full anti­
convulsant effect. Several clinical investigators
have suggested initial loading of selected patients
with phenytoin.12 In one study,2 61 patients re­
ceived a 1-g loading dose of phenytoin followed
by a constant daily maintenance dose of 300 to 400
mg. Seizure control was obtained promptly in all
patients who responded to the drug. Patients tol­
erated the loading doses well, and therapeutic
phenytoin levels were achieved rapidly. Studies in
children have confirmed the efficacy but have
raised questions regarding the safety of this ap­
proach.3
It is well recognized that more than a week of
treatment with a given maintenance dose of gua-
nethidine may be required to produce the maximum
antihypertensive effect of this dose. This results
from the fact that elimination of the dmg from the
body is slow (average half-life about 5 days). A
regimen has been devised for achieving the phar­
macologic effects of guanethidine relatively rap­
idly, using the concept of loading and maintenance
doses based on the kinetics of guanethidine elim­
ination.4 This regimen was tested in 6 hypertensive
patients. Reduction of blood pressure was achieved
with individualized divided loading doses of 150
to 525 mg guanethidine administered over a period
of 1 to 3 days. Maintenance doses ranging from
20 to 65 mg per day were calculated from the
loading dose by assuming a daily loss of about one
seventh of the body stores of drug. Satisfactory
control of blood pressure was maintained following
the guanethidine load, without side effects.
Dosing Interval
The frequency of dosing is often based on tra­
dition and usage (e.g., the t.i.d. orq.i.d. regimen).
From a pharmacokinetic point of view, however.
 Inlroduction to Pharmacokinetics
a rational dosing interval for most drugs approxi­
mates the biologic half-life. Thus, it has been found
that the traditional 3-times-a-day dose of pheny­
toin, a drug with an average half-life of about one
day, is unnecessary in many patients and that the
total daily dose can often be administered once a
day.5
Similar conclusions have been reached with re-
spect to dosing of griseofulvin. Comparable steady-
state plasma levels of griseofulvin are achieved
whether the drug is given in doses of 125 mg 4
times a day or in a single daily dose of 500 mg.6
Apparently, treatment with griseofulvin can be
simplified to once-a-day administration with no
loss of efficacy or safety.
Many neuroleptics and tricyclic antidepressants
have rather long biologic half-lives. Almost from
the beginning of psychopharmacotherapy, certain
clinicians have recognized that the traditional t.i.d.
or q.i.d. division of drug administration is not as
necessary as generally believed and that single
daily doses are sufficient for many patients, par­
ticularly those on maintenance therapy.7
For the past 15 years, the most commonly used
dosage of allopurinol has been 100 mg 3 times a
day. Although the half-life of allopurinol is only
about 1 hr, the half-life of its active metabolite,
oxypurinol, is much longer, about 30 hr. In rec­
ognition of this, it has been suggested that allo­
purinol be administered as a single daily dose.
When 300 mg of allopurinol given in a single daily
dose was compared with 100 mg given 3 times a
day, it was found to be equally effective in reducing
and controlling uric acid levels and equally well
tolerated.8'9 A more recent study confirmed these
results and found that 27 of 33 patients preferred
the once-a-day regimen to the divided-dose regi-
13
men because it was easier to remember or easier 3
to take and more convenient.'0 J
JL
Less frequent dosing may not be feasible with
some rapidly absorbed drugs that produce high
peak concentrations in the plasma, resulting in
adverse effects. This problem may be overcome
by using slow-release dosage fonns. Thus, slow-
release forms may be rational even for some drugs
with long biologic half-lives. Presumably, once-a- 1
day dosing of griseofulvin and certain phenytoin
products is well tolerated because these drugs are
absorbed rather slowly. High doses of most neu­
roleptics and tricyclic antidepressants tend to sedate
and, for most patients, late evening administration
of the total dose is preferable. This may offer the
additional advantage of avoiding the need for a
hypnotic drug.
i
REFERENCES
1. Kutt, H., et al.: Diphenylhydantoin metabolism, blood lev­
els, and toxicity. Arch. Neurol., 11:642, 1964.
2. Wilder, B.J., Serrano, E.E., and Ramsay, R.E.: Plasma
diphenylhydantoin levels after loading and maintenance
doses. Clin. Pharmacol. Ther., 14:191, 1973.
3. Wilson, J.T., Hojer, B., and Rane, A.: Loading and con­
ventional dose therapy with phenytoin in children: Kinetic
profile of parent drug and main metabolite in plasma. Clin.
Pharmacol. Ther., 20;48, 1976.
4. Shand, D.G., et al.: A loading-maintenance regimen for
more rapid initiation of the effect of guanethidine. Clin.
Pharmacol. Ther., /S:139, 1975.
5. Buchanan, R.A., et al.: The metabolism of diphenylhy­
dantoin (dilantin) following once-daily administration.
Neurology, 22:1809, 1972,
6. Piatt, D.S.: Plasma concentrations of griseofulvin in human
volunteers. Br. J, Dermatol., Si:382, 1970.
7. Ayd, F.D,: Once-a-day neuroleptic and tricyclic antide­
pressant therapy. Int, Drug Ther. Newsletter, 7:33, 1972.
8. Brewis, I., Ellis, R.M., and Scott, S.T.: Single daily dose
of allopurinol, Ann. Rheum, Dis., 341:256, 1975.
9. Rodman, G.P., et al.: Allopurinol and gouty hyperuri­
cemia. Efficacy of a single daily dose. JAMA, 2i/:1143,
1975.
10. Currie, W.J.C., Turner, P., and Young, J.H.: Evaluation
of once a day allopurinol administration in man. Br. J.
Clin. Pharmacol,, 5:90, 1978, ;
i
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.
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